The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes.

Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Effects of ALS-associated 5'tiRNA on the transcriptomic and proteomic profile of primary neurons in vitro.

tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples.

Single-cell RNA seq-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma.

Background & Aims: The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit versus resistance to atezo+bev.

TKI resistance in brain metastasis: A CTLA4 state of mind.

Resistance to tyrosine kinase inhibitors (TKIs) in lung cancer brain metastasis (LCBM) remains a clinical challenge. Recently in Cancer Cell, Fu et al. reveal how TKIs reshape the immune microenvironment of LCBM and propose CTLA4 blockade as a promising strategy to overcome resistance.

Associations of the gut microbiome with outcomes in cervical and endometrial cancer patients treated with pembrolizumab: Insights from the phase II PRIMMO trial.

Background: The phase II PRIMMO trial investigated a pembrolizumab-based regimen in patients with recurrent and/or metastatic cervical (CC) or endometrial (EC) carcinoma who had at least one prior line of systemic therapy. Here, exploratory studies of the gut microbiome (GM) are presented.

Methods: The microbial composition of 77 longitudinal fecal samples obtained from 35 patients (CC, n = 15; EC, n = 20) was characterized using 16S rRNA gene sequencing.

Protocol for whole-slide image analysis of human multiplexed tumor tissues using QuPath and R.

The spatial organization of cells within tissues aids in understanding physiological and pathological processes, as well as elucidating the mechanisms of action underlying treatments. We present a protocol for analyzing image-based spatial proteomics data. To illustrate, we focus on whole-slide images of human multiplexed tumor tissues acquired using the PhenoCycler-Fusion 2.

Cabozantinib Induces Isolated Hyperbilirubinemia in Renal Cell Carcinoma Patients carrying the UGT1A1*28 Polymorphism.

Background: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.

Methods: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia.

Applications of single-cell multi-omics in liver cancer.

Primary liver cancer, more specifically hepatocellular carcinoma (HCC), remains a significant global health problem associated with increasing incidence and mortality. Clinical, biological, and molecular heterogeneity are well-known hallmarks of cancer and HCC is considered one of the most heterogeneous tumour types, displaying substantial inter-patient, intertumoural and intratumoural variability. This heterogeneity plays a pivotal role in hepatocarcinogenesis, metastasis, relapse and drug response or resistance.

Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation.

Background & Aims: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD).

Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.

To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled.

A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma.

An important challenge in the real-world management of patients with advanced clear-cell renal cell carcinoma (aRCC) is determining who might benefit from immune checkpoint blockade (ICB). Here we performed a comprehensive multiomics mapping of aRCC in the context of ICB treatment, involving discovery analyses in a real-world data cohort followed by validation in independent cohorts. We cross-connected bulk-tumor transcriptomes across >1,000 patients with validations at single-cell and spatial resolutions, revealing a patient-specific crosstalk between proinflammatory tumor-associated macrophages and (pre-)exhausted CD8 T cells that was distinguished by a human leukocyte antigen repertoire with higher preference for tumoral neoantigens.

Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure.

Background And Aims: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and nonrecovery in ACLF.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10).